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mTOR inhibition protects diabetic heart against ischemia/reperfusion injury through STAT3 activation (1078.5)
Author(s) -
Das Anindita,
Salloum Fadi,
Durrant David,
Samidurai Arun,
Kukreja Rakesh
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1078.5
Subject(s) - cardioprotection , stat3 , pi3k/akt/mtor pathway , ischemia , medicine , reperfusion injury , myocardial infarction , apoptosis , protein kinase b , pharmacology , chemistry , biochemistry
Objective: Diabetes is a major risk factor for myocardial infarction. Rapamycin, mTOR (mammalian target of rapamycin) inhibitor, preserves cardiac function and reduces infarct size after myocardial infarction through STAT3 activation. Recent evidence showed decreased levels of activated STAT3 in diabetic heart. Considering the cardioprotective role of STAT3, we tested the hypothesis that chronic treatment with Rapamycin would protect the diabetic heart against ischemia/reperfusion (I/R) injury through STAT3 signaling. Methods and Results: Adult male wild type or db/db mice were treated daily for 28 days with vehicle (DMSO) or Rapamycin (0.25 mg/kg/day, i.p.). Following treatment, the hearts were subjected to global I (30 min) and R (1 hour) in Langendorff mode. Rapamycin treatment increased STAT3 phosphorylation, reduced infarct size following I/R (Fig. 1A), and protected adult cardiomyocytes following simulated ischemia/reoxygenation in vitro. Downstream targets of STAT3, miRNA‐17 and ‐20a, part of miRNA‐17‐92 cluster, were induced in heart (Fig. 1B, C) and cardiomyocytes derived from Rapamycin‐treated db/db mice. Rapamycin treatment also caused reduced expression of pro‐apoptotic prolyl hydroxylase Egln3/PHD3, a target of miR‐17/20a (Fig. 1D). In addition, Rapamycin‐induced protection against I/R injury was abolished in cardiac‐specific STAT3‐deficient mice made diabetic with high fat diet (Fig. 1E). Conclusion: We conclude that Rapamycin causes STAT3‐miRNA‐20a‐mediated suppression of Egln3/PHD3 that may be associated with cardioprotection against I/R injury in diabetic mice. $graphic_C467787D‐4171‐40BD‐9D1A‐4E6B545698D5$ Grant Funding Source : Supported by NIH HL51045, HL79424, HL118808